ABSTRACT Obesity is a worldwide public health problem, and its incidence is increasing at an alarming rate. Obesity associates with increased risk and worse prognosis of many malignancies including pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms are poorly understood. Obesity induces a pro-inflammatory state both locally in adipose tissue and systemically in visceral organs such as the pancreas. PDAC is a highly desmoplastic/fibrotic tumor in which angiotensin II receptor 1 (AT1) signaling activates pancreatic stellate cells (PSCs), contributing to solid stress (the mechanical force exerted by the solid components of the tumor). We have recently shown that obesity- induced inflammation worsens the desmoplastic tumor microenvironment (TME), and compromises perfusion, oxygenation and chemotherapy in PDACs (Cancer Discovery 2016). Our preliminary data suggest that obesity increases tumor stiffness and solid stress, which compress blood vessels and hinder the delivery and efficacy of cytotoxic therapy. The desmoplastic reaction also promotes pro-survival signaling in cancer cells. We also found crosstalk between fibrotic (AT1) and inflammatory (interleukin-1? (IL-1?)) signaling pathways in PDACs in obese mice. These abnormalities also promote immunosuppression. Building on these exciting findings, we will further dissect molecular and mechanical mechanisms and develop novel strategies to overcome these obesity-induced biomechanical barriers to successful therapy in PDACs. We hypothesize that targeting AT1 and/or IL-1? will alleviate obesity-induced desmoplasia and reprogram the immune TME. To this end, we will study spontaneous and orthotopic PDAC mice with diet-induced obesity (DIO) in both primary and liver metastasis settings. These PDAC models have successfully recapitulated clinical disease. We will characterize mechanical properties of PDACs in DIO using a newly developed approach together with the assessment of biochemical and cellular microenvironment. We will assess the effect of novel TME-activated AT1 blockers (TMA-ARBs), which allow delivery of high-dose ARBs to tumors while avoiding systemic hypotension We will also study the FDA approved IL-1 receptor antagonist (IL-1Ra, anakinra) on obesity-altered PDAC biomechanics, and on inflammatory cytokines and cells in obesity (Aim 1). We will evaluate if TMA-ARBs/ IL-1Ra can reprogram immune TME in PDACs with obesity (Aim 2). Finally, we will determine how elevated solid stress and stiffness alter tumor cells and host stromal cells using in vitro engineered microenvironments with the results being tested in vivo (Aim 3). We anticipate that TMA-ARBs and/or IL-1Ra will alleviate desmoplasia and inflammation in PDACs in obese mice, reprogram ECM and immune TME and facilitate both conventional chemotherapy and immune checkpoint blocker immunotherapy. If successful, these studies will lead to the development of novel treatment strategies for obese PDAC patients. These novel treatments can be rapidly translated into the clinic based on our track record of successful clinical translation in collaboration with outstanding clinicians.